Progressive conduction system disease preceding hypertrophy in IVS4+919G>A Fabry variant: a population-based electrocardiographic study

The IVS4+919G>A variant is the most prevalent late-onset Fabry variant in East Asian populations, but its electrophysiological trajectory remains incompletely defined.

From a regional genetic screening programme, 905 IVS4+919G>A carriers were identified among 457 581 patients and matched 1:2 to controls by age and sex. Electrocardiographic (ECG) parameters were compared across decades, and echocardiography correlated structural changes with ECG findings. The cumulative prevalence of IVS4+919G>A was 0.198%. Age-specific prevalence in females was ∼2.5-fold higher than in males (0.11–0.15%), without significant change throughout different age categories. Female carriers demonstrated the catch-up phenomenon after the age of 60. Males exhibited a nine-fold risk of right bundle branch block and pacemaker implantation compared with male controls (right bundle branch block, HR 9.286, 95% CI 5.16–16.70, P < 0.001; pacemaker implantation, HR 9.197, 95% CI 2.88–29.31, P < 0.001), and this precedes the onset of echocardiographic left ventricular hypertrophy. Risk of stroke and atrial fibrillation (HR 1.435, 95% CI 0.69–2.96, P = 0.289) was similar between male carriers and controls. PR interval did not shorten but was prolonged instead. Combining left ventricular hypertrophy with conduction abnormalities, ECG detection achieved 88% sensitivity, exceeding echocardiographic criteria alone (51.5%).

The IVS4+919G>A variant is characterized by a progressive electrical phenotype dominated by conduction system disease preceding hypertrophy without excess major arrhythmic events. Electrocardiographic surveillance and phenotype-based risk stratification may be more informative than structural assessment alone for identifying individuals at risk of device therapy.

Institutional Review Board: CMUH113-REC3-076